Pharmaceutical packaging in pride of place

An impressive number of entries were received for the Packaging Innovation category in the 2013 CPhI Pharma Awards. Hilary Ayshford, who was on the judging panel, looks at what made the winner and the two runners-up stand out from the crowd

A rigid PVC layer forms an additional reinforced pocket that both protects the tablet and allows it to be pushed through the foil without breaking

In pharma, as in many other industry sectors, it is a sad fact that while enormous effort goes into developing a product, the packaging of that product is often an afterthought, left until the latter stages of the development cycle. But in many cases, and in the pharma industry in particular, the pack can add significantly to the functioning of the product and could make the difference between market success or failure.

The importance of taking the packaging into account at an early stage was amply demonstrated by the three companies shortlisted in the Packaging Innovation category in the CPhI Pharma Awards last October. In all three cases the pack complemented the product and added to its functionality by fulfilling an unmet need.

The winner was Italian company E-Pharma Trento, which found a solution to the challenge of packaging its orodispersible tablets (ODTs) in blisterpacks. Dysphagia is a major problem for many elderly patients, and the growth in easy administration forms such as ODTs is set to accelerate.

Orally disintegrating tablets have to dissolve quickly in the mouth without the administration of water. They should have enough mechanical characteristics to withstand the packaging operations, but on the other hand they should be soft enough to dissolve quickly in the mouth.

This means that ODTs are much more friable and fragile than standard solid dosage forms, and tend to break when packed in standard push-through blisters. But the current alternative of a peelable blisterpack is not intuitive and may result in damage to the blister, leaving uncovered more than one tablet, tablet breakage and the consequent risk of incorrect administration or accidental ingestion of part of the packaging. The challenge, therefore, was to develop a user-friendly push-through blister able to protect the fragile tablets.

A rigid PVC layer in the form of additional reinforced pockets both serves as a push-through device and protects the individual tablets

E-Pharma Trento’s pack consists of three layers rather than the usual two, the innovative aspect being the introduction of a rigid PVC layer in the form of additional reinforced pockets that serve as a push-through device and protect the individual tablets from breaking. The pack has been granted a European patent and patents are pending in the US and in Canada.

The company worked in collaboration with a leading Italian machinery manufacturer to develop an innovative and highly flexible packaging line capable of producing both the new blisterpack and standard Alu-Alu blisters. The production process for the strengthened blisterpack is based on a two-step sequence, in which two conventional blister machines are coupled together, guaranteeing the required productivity levels but also perfect tablet quality.

When a standard Alu-Alu blister is required, the line can be quickly modified to achieve a high speed output comparable to other similar machines available on the market. In this way E-Pharma Trento gained the advantages of a multipurpose line, combining a minimum number of customised parts needed for the new blisterpack production (and keeping related costs at a minimum) with the potentialities of a typical Alu-Alu package line. The new production line was installed in the company’s plant in Trento at the end of 2012, authorised by the Italian Medicine Agency (AIFA) and is now operative.

E-Pharma has an ODT packed in this new kind of reinforced blister that was scheduled to go into commercial production by the end of last year. Other pharma products are currently under development. At the same time, the company is investigating the possibilities of expanding the use of this innovative packaging outside pharma, promoting and offering the use of the patent in other fields where the fragility of the product requires a reinforced blister package. Interest from the market is reported to be very high.

Ophthalmic dispensing

One of the runners-up, Bangalore-based packaging and medical device manufacturer Doctor Pack India, also adopted a new approach to dispensing a conventional dosage form – in this case sterile ophthalmic drops. The packaging and dispensing of liquid ophthalmic preparations has traditionally presented a number of challenges with regard to preserving the sterility of the medication and preventing contamination while still allowing the patient to open the pack and administer the product accurately and at the correct dose.

According to G Dinakaran, Chairman and Managing Director of Doctor Pack India, there are three main options widely used today. The first is a three-component container/closure system consisting of a squeezable plastics bottle; an open nozzle and a cap. The second consists of a squeezable plastics bottle with a sealed nozzle manufactured using blow/fill/seal (BFS) technology; and a closure that incorporates a method of piercing the nozzle. The final option is another three-part container/closure solution consisting of a squeezable plastics bottle, a closed nozzle and a piercing cap.

The closed container systems are the preferred options as they eliminate the risk of sterility failure or leakage due to improper capping in the assembly machine. But once the product is in the hands of the end user, the sealed nozzle options present new challenges because the patient must pierce the diaphragm.

Finding that the bottle is still sealed, the patient is likely to resort to any available tool to pierce the diaphragm, thereby contaminating the dispensing tip as well as the contents

The conventional piercing cap, which the patient must first tighten fully to pierce the diaphragm to enable the medication to be dispensed has several drawbacks. The first is that the end user is confused by the need to tighten the cap down before unscrewing it as this is contrary to standard practice.

Finding that the bottle is still sealed after the cap has been removed in the conventional way, the patient is likely to resort to any available tool such as a non-sterile pin or needle or scissors to pierce the diaphragm, thereby contaminating the dispensing tip as well as the contents. The second disadvantage is that the drops that are dispensed by such packs will have variable microlitre dose delivery depending on the squeeze force applied by the patient, leading to over- or under-dosing with potentially serious side-effects, wastage and increased cost of treatment. The third drawback is that during filling and assembly accidental pre-piercing of the nozzle can occur, leading to leakage in the market as well as rendering the content non sterile.

With a view to overcoming these hazards, Doctor Pack developed Magic Cap, which has an automatic mechanism to pierce the sealed diaphragm of the bottle or the nozzle, just by opening the cap for dispensing. Furthermore, it delivers controlled microlitre drops.

On opening the Magic Cap in the same way as a standard closure, the ratchet on the outer cap drives down the inner cap. The inner cap detaches and drives a spike down onto the bottle tip diaphragm, piercing it and creating an opening that allows only a specific dose to be dispensed. The inner cap is then locked onto the bottle tip and is retained as part of the container

Manufactured in a validated cleanroom, the Magic Cap consists of an outer and inner cap that are preassembled and supplied as a single component. It is suitable for use on standard capping machines and there is no chance of pre-piercing the diaphragm during high-speed assembly.

When the patient removes the closure by unscrewing the outer cap, a reverse thread on the inner cap pushes the inner cap downwards to enable the spike to pierce the diaphragm and the medication to be dispensed. The design profile of the inner cap delivers a consistent drop count and minimises under- and over-dose variations. This in turn reduces wastage and makes the product more economical.

The closure is easy to operate and requires no special instructions to be given to the patient. The pilot tool Magic Cap samples were tested on 200 bottles by three different groups of people in different age groups. All were able to open the bottle and dispense the medication without any secondary operation to pierce the nozzle diaphragm.

A number of pharma companies are currently carrying out comprehensive performance studies using the Magic Cap and feedback has been very encouraging, said Dinakaran. The company will be applying for a global patent in the near future and expects the product to be commercially available on the international market from April 2014.

Vaginal applicator

The other runner-up was a vaginal applicator with a unique design that can dispense the medication easily and comfortably with just one hand. The device was developed by BeyonDevices, a spin-off unit of Portuguese company Neutroplast, in response to the growing trend towards using the mucosal route for drug delivery, particularly molecules that are poorly absorbed when taken orally. Despite being a non-invasive route of drug administration, the vagina has not been explored as extensively as other routes. Nowadays, the acceptability of vaginal drug administration by women and doctors is increasing, raising interest for this drug delivery route.

The company says that although vaginal drug delivery was initially restricted to delivery of anti-infectives, there is evidence of significant systemic drug absorption through the vagina that could lead to development of drugs for managing non-vaginal conditions.

Steroid hormones are currently used as contraceptives or in hormonal substitution therapy via the vaginal route, but it also has potential for the delivery of biological molecules, small interfering RNA, oligonucleotides, antigens, vaccines, microbicides and therapeutic proteins and peptides. Besides the advantage of ease of administration and the possibility of auto-administration, the vaginal route minimises the first-pass metabolism through the liver that greatly reduces the bioavailability of the drug. Furthermore, it offers low enzymatic activity and the possibility of preferential transfer of absorbed drugs to the uterus (the ‘first-uterine-pass effect’), which may also benefit drug delivery.

Vaginal applicators are divided into single-use (usually prefilled) and reusable (filled prior to insertion). The majority of designs are barrel-and-plunge and squeeze tubes that are not easy to insert and may have sharp edges. Dosage forms include liquids, ovules, tablets/pills, creams, ointments and gels.

The vaginal applicator is designed for comfortable and safe delivery of multiple dosage forms

The BeyonDevices applicator has no sharp ends and follows the anatomy of the vaginal canal. The wedge-shaped point of the applicator will not dig in as the anatomic shaft follows the natural vaginal contour and the point glides with little effort up the vagina, ensuring safe delivery in the intended location and the avoidance of local trauma associated with insertion. It is capable of handling most dosage forms and uses a novel mechanism to dispense the drug with little pressure using one hand.

A patent application has been filed and accepted. The company was also granted an international design registration. The device has been designed for simplified manufacturing production; a reduced cost of investment; fewer inventory parts; smaller package volume; and reduced transport costs. A prototype batch of BeyonDevices’ vaginal applicator has been manufactured at the company’s facilities and is undergoing initial performance studies and registration/certification testing, together with pharmaceutical partners. The first production batch was expected at the end of 2013.

Manufacturing Chemist will be following the development of all three products with interest, as well as looking forward to the innovations that the 2014 CPhI Pharma Awards will bring.